The objective of this proposal is to translate dualMRI, a new noninvasive method of measuring intervertebral disc (IVD) biomechanics, to humans. IVD degeneration is a common orthopaedic problem, afflicting millions of people in the United States. The IVD pathophysiology involves a degenerative cascade that disrupts normal extracellular matrix protein synthesis and increases the expression of inflammatory cytokines and enzymes. IVD biomechanical function is sensitive to degeneration, with altered internal patterns of three dimensional (3D) strains related to the loss of water content and proteoglycan breakdown in the nucleus pulposus (NP), and loss of structural integrity of the annulus fibrosus (AF). Fortunately, the degenerative cascade gives rise to many potential therapeutic targets. Prior to end-stage treatment (e.g. spinal fusion), numerous possible biological therapies and management strategies for IVD degeneration include stem and autologous cell implantation, gene therapy, prophylactic injection, and IVD denervation. An ideal therapy would ultimately restore the biomechanical function of the IVD, characterized by internal strain fields that reveal local repair and healing following damage. There are currently no in vivo methods available to measure 3D biomechanical function throughout the interior of the IVD. In an effort to develop an imaging biomarker that noninvasively tracks the biomechanical functional of musculoskeletal tissues following therapy, we developed dualMRI (displacements under applied loading by MRI) for the measurement of mechanical strain in the interior of articular cartilage and IVDs. We are now poised to implement dualMRI for the in vivo measurement of biomechanics in volunteers with healthy and degenerated lumbar IVDs. We will establish a working protocol for in vivo dualMRI in human volunteers, including custom mechanical loading methods and MRI pulse sequences, which will readily expand to larger scale pathologic and clinical studies in future applications. We will pursue two Aims. In Aim 1, we will implement dualMRI to measure 3D patterns of human intervertebral disc strain. In Aim 2, we will demonstrate strain differences between healthy and abnormal IVDs in vivo. If successful, we will provide a new tool for the noninvasive and in vivo functional assessment of the IVD. This work will provide musculoskeletal, pharmaceutical, and othopaedic surgery communities with (a) a clinical diagnostic tool to evaluate efficacy of therapeutic agents to target early degeneration in animal and human trials, (b) the ability to functionally evaluate IVD healing and repair with emerging biological therapies, (c) baseline data describing the healthy function of human IVDs in vivo, and (d) a platform technology to more broadly study mechanical function of load-bearing tissues (e.g. meniscus, ligament) in vivo.